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Administrative data

Description of key information

In a 90-day repeated dose toxicity study in rat by gavage, a NOAEL was established at 250 mg/kg bw/d based on reduced

body weight gain, reduced spontaneous activity and increased % reticulocytes.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
good quality (OECD study, GLP)

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral toxicity

In a 90-Day Repeated Dose Oral Toxicity Study (OECD 408, GLP) in Wistar rats with acetophenone at dose levels of 125, 250 and 500 mg/kg body weight/day the following conclusions can be made:

No adverse effects of acetophenone were found at the dose level of 125 mg/kg body weight/day. At a dose level of 500 mg/kg body weight/day statistically significantly lower mean body weight gain was noted in the male HD group (15 % below controls when related to the entire treatment period). No toxicologically relevant effect for body weight was noted for females.

Clinical signs related to the known hypnotic effect of acetophenone were observed mainly in the male and female groups treated with 500 mg/kg body weight/day such as reduced spontaneous activity. Slight effects were also observed transiently in some animals of the MD group during the weekly detailed clinical observation.

At the end of the treatment period, adverse effects on parameters of haematology were noted in the male and female groups at 500 mg/kg body weight/day. A dose dependently higher mean percentage of reticulocytes was observed in all male and female dose groups with achieving statistical significance in all groups except for the female low dose group when compared to the respective controls. Markedly higher values for the male group at 500 mg/kg body weight/day (97 % above controls) and the female group at 500 mg/kg body weight/day (94 % above controls) was considered as adverse effect of the test item. This regenerative response in the male and female groups at 500 mg/kg body weight/day was correlated to an increase in cell volume. Thus, mean corpuscular volume (MCV) was noted to be marginally, but statistically significantly higher in the male group at 500 mg/kg body weight/day (5 % above controls), the female group at 250 mg/kg body weight/day (4 % above controls) and the female group at 500 mg/kg body weight/day (5 % above controls). In correlation to the regenerative response, marginally but statistically significantly lower red blood cell count and haemoglobin were observed in the female group at 500 mg/kg body weight/day (7 % and 5 % below controls, respectively). Slight changes for parameters of haematology in the male and female groups at 125 and 250 mg/kg body weight/day were well within historical control data and not considered to be in a toxicological relevant range.

Acetophenone caused in the liver a minor hepatocellular hypertrophy in animals of all test item treated groups which was correlated to a significantly higher liver weight in the male and female groups at 250 and 500 mg/kg body weight/day when compared to the respective controls. Without accompanying lesions, this was considered as an adaptive metabolic effect. Secondary to the liver lesions, a minimal diffuse follicular hypertrophy in one female at 250 and few animals at 500 mg/kg body weight/day was observed which is known not to be of relevance for human. Furthermore, stress related lesions (minimal diffuse cortical hypertrophy in the adrenal glands at 250 and 500 mg/kg body weight/day and minor atrophy of the thymus in all dose groups) were not considered as adverse effect. Hyaline inclusions in male kidneys from animals of all test item treated groups corresponded with the presence of α2-microglobulin which was statistically significantly higher in the male groups dosed with 250 and 500 mg/kg body weight/day compared to controls. This is a typical issue in male rats and was considered as a non-adverse metabolic change as there were no further lesions in the kidneys.

The NOAEL in this study was considered to be 250 mg/kg body weight/day. Based on the histopathological findings the NOEL of acetophenone could not be established.

In a combined repeated dose toxicity and reproduction/developmental screening study according to OECD Guideline 422 with gavage exposure (>46d) to doses of 0, 75, 225 and 750 mg acetophenone/kg bw/day the overall LOAEL for male and female rats was 750 mg/kg bw/day based on clinical and neurobehavioral findings and biochemical changes. The NOAEL was 225 mg/kg bw/day (key study, Thorsrud 2003).

Dermal toxicity

No sub-acute or sub-chronic repeated dose toxicity studies are available for dermal route. Based on a comparison of LD50 values for oral and dermal application of 2081 and 3300 mg/kg bw (key studies from section 7.2.1 and 7.2.3), absorption by dermal rout seems to be lower than by oral route. Thus we can expect that long-term dermal toxicity will be lower than long-term oral toxicity (or in a worst case equal). The difference between the LOAELs for acute clinical symptoms with values of 710 and 1,820 mg/kg bw for oral and dermal application is even greater (2.56 fold) and confirm this hypothesis. Consequently, the NOAEL after dermal application is expected to tend to a lower value than after oral application and the performance of a repeated dose toxicity study by dermal application can be waived.

As exposure may occur by dermal route during manufacture and use, a DNEL by dermal route will be extrapolated from results obtained by oral route (route-to-route extrapolation).

Consequently, the NOAEL after dermal application is expected to tend to a lower value than after oral application and the performance of a repeated dose toxicity study by dermal application can be waived.

Additionally, there is no adverse effect reported in cosmetovigilence.

Inhalation toxicity No sub-acute or sub-chronic repeated dose toxicity studies are available for inhalation route. However this study can be waived based on column 2 adaptation (Reach regulation, Annex VIII, section 8.6) and because exposure of humans via inhalation is unlikely; handling of the registered substance does not produce vapour, aerosols or droplets.

Justification for classification or non-classification

All study results lead to no classification of acetophenone according to CLP criteria: sub-chronic oral (gavage) toxicity study (reliability 1), supported by OECD 422 study (oral, gavage, reliability 1) gave fully consistent results, leading to a NOAEL of 250 mg/kg/d, far higher than STOT RE Category 2 upper threshold of 100 mg/kg/d.

Thus no classification is required according to EU regulation 1272/2008.